The Lupus Book: A Guide for Patients and Their Families, Third Edition (8 page)

HLA testing is very simple. Your physician needs only a few tubes of blood

drawn from the arm. Its applications for lupus are not reliable yet, but once

scientists find out a bit more about which types of disease are associated with

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What Causes Lupus?

which genes, HLA blood testing will come down to an issue of cost and become

more widespread.

The HLA site consists of three well-defined and functionally distinct regions

known as classes I, II, and III. Class I is expressed on all cells with a nucleus and is divided into A, B, and C subtypes. Class II is present on cells that are capable of presenting antigens (foreign material) to white blood cells and includes the D subtype. The D regions are further broken down into DP, DQ, and

DR subregions, among others. Class III provides for the structural genes that

produce a variety of substances important in lupus blood and tissues such as

complement, tumor necrosis factor, and heat shock protein.

An HLA ‘‘marker’’ is given to patients based on the subtype they possess,

A, B, C, or D. Numerous
alleles
(‘‘designations’’ or ‘‘arrangements’’) can be found at the same marker or site; there are more than a hundred possible arrangements that are further subdivided. If this seems complicated, don’t worry.

This expanding area of knowledge often confuses the best immunologists and

rheumatologists.

A combination of alleles at two HLA loci are name tags, or
haplotypes
. They can differ widely among various racial and ethnic groups. For example, HLA-B27 (the marker associated with a spinal disease known as ankylosing spon-

dylitis) is found in 8 percent of Americans of European Caucasian ancestry but

is very rare among African Americans.

The statistical chance that two particular haplotypes will occur together is

about 2 percent (for example, A6 with B5). However, in certain rheumatic dis-

eases, the chance that two alleles or arrangements will occur together may

greatly exceed this.

Table 7.1 illustrates the classification of the HLA system. The labels them-

selves are not important for our purposes; what is important is that specific genes are inherited and these may predispose a person to lupus.

Table 7.1.
The HLA Region of the Major

Histocompatibility Complex

Class I (on all nucleated cells)

A markers

B markers

C markers

Class II (on all antigen-presenting cells)

DP markers

DQ markers

DR markers

Class III contains structural genes that produce

chemicals important in lupus, such as

Complement

Hormones

Cytokines

The Genetic Connection

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WHY IS HLA IMPORTANT IN LUPUS PATIENTS?

What does all this mean for lupus? First of all, certain
subsets
of the disease are associated (in other words, they are often but not always found) with very

specific
HLA markers. For instance, neonatal lupus (lupus afflicting children at birth) is most often present in children who possess the A1, B8, DR3, and

DQw52 haplotypes. Patients with discoid lupus tend to possess DR4 markers,

and DR3 is present in those with a specific skin problem known as subacute

cutaneous lupus. Sjo¨gren’s syndrome (dry eyes, dry mouth, and arthritis, which is seen in many patients with SLE) is associated with B8, DR3, and DRw52.

DR2 and DR3 are more commonly observed in Caucasians of Western European

descent than any other DR types. The presence of DQw1 correlates with certain

autoantibodies such as anti-DNA, anti-Ro, and anti-La. ‘‘Null’’ or absent alleles can account for some of the deficiencies in blood complement levels that are

frequently seen in SLE.

Even though we have yet to isolate a lupus ‘‘gene,’’ certain genetic markers

and other non-HLA genes correlate with specific lupus subsets and autoanti-

bodies. Different sets or combinations of genes may be associated with as much

as a twentyfold risk for developing SLE.

OTHER LUPUS SUSCEPTIBILITY GENES

A variety of genes outside of the HLA system may predisopose individuals

to SLE. These include genes on mannose binding protein, Fc receptor alleles,

immunoglobulin G receptors, T-cell receptors, those involved with apoptosis,

and genetic polymorphisms associated with cytokines (particularly tumor necro-

sis factor alpha, apoptosis, interleukin-6, and interleukin-10). Under the direction of Dr. Betty Tsao, our group at UCLA was the first to suggest that a set of

genes on the short arm of chromosome 1 contributes approximately 20 percent

of the risk for SLE. More recently, scientists have started performing ‘‘genome scanning,’’ or looking at all of our chromosomal regions which might be linked

with lupus.

WHAT IS THE RISK THAT A MEMBER OF A LUPUS

PATIENT’S FAMILY WILL DEVELOP LUPUS?

If you have lupus, members of your immediate family, or first-degree relatives

(brothers, sisters, parents, and children), are at a slightly increased risk for developing it too. Several surveys have estimated this risk at 10 percent for your daughter and 2 percent for your son. If you have lupus and have an identical

twin, the chance that this sibling is similarly afflicted ranges from 26 to 70

percent. If your twin is fraternal, however, this figure is only 5 to 10 percent.

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What Causes Lupus?

Interestingly, the prevalence of SLE among all family members of lupus patients is 10 to 15 percent, while the chance of any of this group having autoimmune

diseases (including lupus) is 20 to 30 percent. The most common other auto-

immune disorders include autoimmune thyroiditis (also known as Graves’ dis-

ease or Hashimoto’s thyroiditis), rheumatoid arthritis, and scleroderma. The

body may produce elevated levels of autoantibodies even though no specific

immune disorder is present. For example, nearly half the first-degree relatives of my lupus patients may have a positive ANA blood test. However, ANA is

only one of the four criteria that must be present for SLE to be diagnosed.

Whether or not a positive ANA increases the chance of developing lupus isn’t

known; most ANA-positive family members of lupus patients feel well and have

no symptoms.

Should children of lupus patients or family members be ‘‘typed’’ or screened

for SLE? I don’t recommend testing unless symptoms or signs point to some

existing clinical problem. At this time, there is nothing we can offer those who carry a lupus ‘‘gene’’ or autoantibody and have no symptoms. In other words,

by testing them, we would only make them anxious or worried. Only a small

percentage of these individuals will ever develop the disease.

THE FUTURE

It is very possible—indeed probable—that in the next 30 years we will be able

to identify patients at risk for developing SLE by using HLA testing or other

methods and that we’ll then vaccinate them to prevent lupus. By that time, all

lupus-causing genes will have been isolated and identified. Potentially this would allow us to manipulate these genes in patients with active SLE to turn off the

disease process.

8

Environmental Villains

Many of my newly diagnosed lupus patients examine everything they have done

or experienced regarding travel, prescription medications, occupational activi-

ties, infections, and other factors in an effort to find a reason for their disease.

In my experience, some individuals are convinced that they did something

‘‘wrong’’ and therefore became ill. When this occurs, soul searching represents a natural process that ultimately results in coming to terms with the diagnosis.

Although the precise cause of lupus is not known in each case, there are indeed certain environmental factors that may occasionally play a role in initiating the disease or making it worse. How does this happen?

A few of these mechanisms are linked to environmental factors and may

produce effects in a variety of ways. These include a virus, food, or a chemical acting as an antigen to which an antibody response is generated. Some of these

agents in patients predisposed to lupus mimic antigens to which the body is

sensitized, and the antibody response is wrongly directed against the environ-

mental factor. Alternatively, an antigen or inciting factor such as ultraviolet sunlight can damage DNA and promote the production of anti-DNA as an immune response to the altered DNA.

Various medications may also play a role in inducing lupus. Drug-induced

lupus is covered in the next chapter.

This chapter concerns itself with four types of potentially inciting agents: (1) chemical factors, such as chemical agents, metals, and toxins; (2) dietary factors, such as amino acids, fats, and caloric intake; (3) ultraviolet radiation; and (4) infectious agents, such as viruses and bacteria as well as their by-products.

WHAT CHEMICAL FACTORS CAUSE LUPUS?

Aromatic Amines

Aromatic amines
are chemical agents that may induce or aggravate rheumatic disease. This class includes
hair-coloring solutions, hydrazines
(e.g., tobacco smoke), and
tartrazines
(e.g., food colorings or medication preservatives). Ar-

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What Causes Lupus?

omatic amines are broken down in the body by a process known as
acetylation
.

An increased incidence of drug-induced lupus has been observed after exposure

to aromatic amines in patients who are
slow acetylators
, or those who metabolize aromatic amines slowly. About half of all Americans are slow acetylators. The

mechanism by which aromatic amines may induce an immunologic reaction is

poorly understood, and only a small percentage of people exposed to these

chemicals ever develop clinical immune disease.

Hair-coloring solutions
containing aromatic amines, specifically paraphen-ylenediamine, can reproduce features of autoimmune disease in experimental

animals. Several large-scale epidemiologic surveys that that have tried to find out whether aromatic amines induce lupus or cancer have yielded conflicting

results. Do I advise my lupus patients to avoid hair dyes? No, since I rarely see patients who reported a flareup because they used a hair-care product; also, they already have the disease when they visit me.

Hydrazines
are present in hydralazine, a blood pressure medication known to induce lupus. In addition, these substances are found in a variety of compounds used in agriculture and industry and occur naturally in tobacco smoke and mush-rooms. A single published report tells of a pharmaceutical worker who was

occupationally exposed to hydrazines, developed lupus, and had reproducible

symptoms and signs upon repeated exposure.

Tartrazines
are preservatives found in certain food dyes (such as FD&C yellow No. 5), tattoos, and in some medicine tablets. Occasional well-documented

reports of tartrazine-induced lupus have appeared.

Silica and Silicone

One of the most ubiquitous elements in nature, silicon, has been the focus of

numerous studies. Nearly 50 years have elapsed since the initial observations

that sandblasters exposed to
silica dust
may develop an autoimmune type of reaction characterized by lung nodules and scarring as well as autoimmune-mediated lesions in the kidney.

The injection of
silicone
, a synthetic liquid form of silicon, under the skin has been similarly associated with autoimmune reactions. According to some

scientists but not all, silicone may be broken down into silica in the body. A

few women who have undergone breast augmentation with encapsulated silicone

gel implants have developed a lupus-like disease; this is probably coincidental.

Other Chemicals

Some chemicals can produce lupus-like symptoms as part of other diseases.

Scleroderma
is a first cousin of lupus, and many overlapping features are present in both diseases. But the principal difference is that, with scleroderma, the in-Environmental Villains

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flammation heals with scarring and tightening of the skin. The development of

diseases like scleroderma has been associated with a variety of chemicals, in-

cluding polyvinylchloride, trichloroethylene, cocaine, appetite suppressant am-

phetamines, and adulterated cooking oils (i.e., an epidemic caused by denatured rapeseed oil—‘‘toxic oil syndrome’’—afflicted 15,000 people in Spain in the

early 1980s and several hundred of them died).

Autoimmune diseases resembling lupus have been found in animals exposed

to certain
metals
, including mercuric chloride, gold, and cadmium. No human reports have appeared as yet. Eosin is a chemical contained in
lipstick
that may trigger sun-sensitivity rashes and allergic dermatitis. A widely cited report speculating on a role for lipstick in the causation of lupus appeared 30 years ago, but follow-up studies have suggested that there is no connection.

SHOULD LUPUS PATIENTS AVOID ANY

FOODS OR SUPPLEMENTS?

Foods are made up of three principal components: carbohydrates, proteins, and

fat. Thus, dietary manipulations can include either altering these components or raising or lowering overall caloric intake. Studies conducted on mice with lupus have suggested that high-calorie diets may accelerate mouse kidney disease, but there is no evidence that this occurs in humans. On the other hand, while ‘‘star-vation’’ low-calorie or low-fat regimens help mice with lupus, they can occa-